Vantobra 170mg1.7ml nebuliser solution 1.7ml ampoules

United Kingdom - English - MHRA (Medicines & Healthcare Products Regulatory Agency)

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Active ingredient:
Tobramycin
Available from:
Pari Medical Ltd
ATC code:
J01GB01
INN (International Name):
Tobramycin
Dosage:
100mg/1ml
Pharmaceutical form:
Nebuliser liquid
Administration route:
Inhalation
Class:
No Controlled Drug Status
Prescription type:
Valid as a prescribable product
Product summary:
BNF: 05010400; GTIN: 9120073453013

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Package leaflet: Information for the patient

Vantobra

170 mg nebuliser solution

Tobramycin

Read all of this leaflet carefully before you start using this medicine because it contains important

information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor, or pharmacist.

This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if

their signs of illness are the same as yours.

If you get any side effects, talk to your doctor, or pharmacist. This includes any possible side effects

not listed in this leaflet. See section 4.

What is in this leaflet

What Vantobra

is and what it is used for

What you need to know before you use Vantobra

How to use Vantobra

Possible side effects

How to store Vantobra

Contents of the pack and other information

1.

What Vantobra

is and what it is used for

What Vantobra

is

Vantobra

contains an antibiotic medicine called tobramycin. It belongs to a class of antibiotic medicines

called aminoglycosides.

What Vantobra

is used for

Vantobra

is used in patients with cystic fibrosis aged 6 years and older to treat lung infections caused by

bacteria named Pseudomonas aeruginosa.

Pseudomonas aeruginosa is a bacterium that frequently infects the lungs of cystic fibrosis patients at some

time during their lives. If the infection is not properly treated, it continues to damage the lungs, causing

further problems with breathing.

How Vantobra

works

When you inhale Vantobra

, the antibiotic can enter directly into your lungs to fight the bacteria causing the

infection. It works by disrupting the production of proteins that the bacteria need to build their cell walls.

This damages the bacteria and eventually kills them.

2.

What you need to know before you use Vantobra

Do not use Vantobra

if you are allergic (hypersensitive) to tobramycin, to any type of aminoglycoside antibiotics, or to any of the

other ingredients of Vantobra

(listed in section 6).

If this applies to you, tell your doctor before using Vantobra

Warnings and precautions

Talk to your doctor if you have ever had any of the following conditions:

hearing problems (including noises in your ears and dizziness);

kidney problems;

chest tightness;

blood in your sputum (the substance you cough up);

muscle weakness that lasts or becomes worse over time, a symptom mostly related to conditions such

as myasthenia (muscle weakness) or Parkinson’s disease.

If any of these apply to you, tell your doctor before using Vantobra

If you have problems with your hearing or kidney function, your doctor may take blood samples to monitor

the amount of Vantobra

in your system.

Inhaling medicines can cause chest tightness due to narrowing of the airways, and this can happen with

Vantobra

. Your doctor may ask you to use other appropriate medicines to widen the airways before using

Vantobra

Strains of Pseudomonas can become resistant to treatment with an antibiotic over time. This means that

Vantobra

may not work as well as it should over time. Talk to your doctor if you are concerned about this.

If you are also taking tobramycin or another aminoglycoside antibiotic by injection, it may increase the risk

of side effects and your doctor will monitor for these as appropriate.

Children

The medicine is not intended for use in children under 6 years of age.

Other medicines and Vantobra

Tell your doctor or a pharmacist if you are taking or have recently taken any other medicines, including

medicines obtained without a prescription.

You should not take the following medicines while you are using Vantobra

furosemide, a diuretic (“water tablet”);

other medicines with diuretic potential such as urea or mannitol;

other medicines which may harm your kidneys or hearing:

amphotericin B, cefalotin, polymyxins (used to treat microbial infections), ciclosporin,

tacrolimus (used to reduce the activity of immune system). These medicines may harm the

kidneys;

platinum compounds such as carboplatin and cisplatin (used to treat some forms of cancer).

These medicines may harm the kidneys or hearing.

The following medicines can increase the risks of harmful effects occurring if they are given to you while

you also take tobramycin or another aminoglycoside antibiotic given by injection:

anticholinesterases such as neostigmine and pyridostigmine (used to treat muscle weakness), or

botulinum toxin. These medicines may cause muscle weakness to appear or become worse.

If you are taking one or more of the above medicines, talk to your doctor before you use Vantobra

You should not mix or dilute Vantobra

with any other medicine in your Tolero

nebuliser handset which is

provided together with Vantobra

If you are taking several different treatments for cystic fibrosis, you should take them in the following order:

Bronchodilator therapy, such as salbutamol

Chest physiotherapy

Other inhaled medicines

Vantobra

Please check this order with your doctor as well.

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your

doctor for advice before using this medicine.

It is not known whether inhaling this medicine while you are pregnant causes side effects. When they are

given by injection, tobramycin and other aminoglycoside antibiotics can cause harm to an unborn child, such

as deafness and kidney problems.

If you are breast feeding, you should talk to your doctor before using this medicine.

Driving and using machines

Vantobra

is not expected to affect your ability to drive or use machines.

3.

How to use Vantobra

Always use this medicine exactly as your doctor has told you. Check with your doctor if you are not sure.

The recommended dose is two ampoules each day (one in the morning and one in the evening) for 28 days.

The dose is the same for all persons aged 6 years and older.

Inhale by mouth the full content of one ampoule in the morning, and one ampoule in the evening using

the Tolero

nebuliser handset.

It is best to have an interval as close as possible to 12 hours between doses, but this interval must be at

least 6 hours.

After you have used your medicine for 28 days, you then have a 28-day break, during which you do not

inhale any Vantobra

. You then start another course after the break (as illustrated).

It is important that you keep using the medicine twice each day during your 28 days on treatment, and

that you keep to the 28-day on / 28-day off cycle.

ON Vantobra

OFF Vantobra

Use Vantobra

twice a day for 28 days

Do not use any Vantobra

for the next 28 days

Repeat cycle

Continue using Vantobra

on this cyclical basis for as long as your doctor tells you.

If you have questions about how long to use Vantobra

, talk to your doctor or pharmacist.

Preparing Vantobra

for inhalation

Use Vantobra

only with the Tolero

nebuliser handset shown in the picture below to make sure you

inhale the correct dose. Do not use the Tolero

nebuliser handset for any other medicine.

Read the Instructions for Use provided with the handset device before use.

Make sure you have an eFlow

rapid or eBase

Controller to connect the Tolero

nebuliser handset.

The respective controller can be prescribed by your physician or purchased separately.

Wash your hands thoroughly with soap and water.

Remove one ampoule of Vantobra

from the aluminium foil pouch just before inhalation.

Keep the rest of the medicine refrigerated in the original carton.

Lay out all the pieces of your Tolero

nebuliser handset on a clean, dry paper or cloth towel. Make

sure the nebuliser handset is on a flat, stable surface.

Assemble the Tolero

nebuliser handset as illustrated in the Instructions for Use of the handset

device.

Hold the ampoule upright and tap lightly before twisting off the head part to avoid spilling. Empty

the contents of one ampoule into the medication reservoir of the nebuliser handset.

Begin your treatment sitting in an upright position, in a well ventilated room. Hold the nebuliser

handset horizontally and breath normally through your mouth. Avoid breathing through your nose.

Continue to inhale and exhale comfortably until the treatment is finished. When all of the medicine

has been delivered, you will hear the “treatment complete” tone.

If you need to interrupt your treatment for any reason, press and hold the On/Off button for one full

second. To re-start the treatment, press and hold the On/Off button again for one full second to

resume treatment.

The Tolero

nebuliser handset must be cleaned and disinfected as described in the instructions for

use of the device.

Use a new Tolero

nebuliser handset for each treatment cycle (28 days on-treatment) as provided

with the medicine.

Do not use an alternative untested nebuliser system because it may alter the amount of medicine reaching the

lungs. This in turn may alter how well the medicine works and its safety.

If you use more Vantobra

than you should

If you inhale too much Vantobra

you may get a very hoarse voice. Tell your doctor as soon as possible. If

Vantobra

is swallowed, it is unlikely to cause severe problems as tobramycin is poorly absorbed from the

stomach, but you should still tell your doctor as soon as possible.

If you forget to use Vantobra

If you forget to use Vantobra

and there are at least 6 hours to your next dose, use your dose as soon as you

can. Otherwise, wait for your next dose. Do not use a double dose to make up for a forgotten dose.

If you stop using Vantobra

Do not stop using Vantobra

unless your doctor tells you to do so, as your lung infection may not be

controlled sufficiently and may become worse.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4.

Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Some side effects can be serious

chest tightness with difficulty in breathing (rare, affecting up to 1 in 1,000 people)

allergic reactions including hives and itching (very rare, affecting up to 1 in 10,000 people).

If you experience any of these, stop using Vantobra

and tell your doctor straight away.

People with cystic fibrosis have many symptoms of the disease. These may still occur while using Vantobra

but should not be as frequent or worse than before.

If your underlying lung disease seems to become worse while you are using Vantobra

, tell your doctor

straight away.

Other side effects may include:

Uncommon (may affect up to 1 in 100 people)

shortness of breath

voice alteration (hoarseness)

increased cough

sore throat

Rare (may affect up to 1 in 1,000 people)

laryngitis (inflammation of the voice box that can cause voice alteration, sore throat and difficulty

swallowing)

Loss of voice

headache, weakness

nosebleed, runny nose

ringing in the ears (normally transient), hearing loss, dizziness

coughing up blood, producing more sputum than normally, chest discomfort, asthma, fever

taste disturbances, feeling sick (nausea), mouth ulcers, being sick (vomiting), loss of appetite

rash

chest pain or general pain

worsening of lung function test results

Very rare (may affect up to 1 in 10,000 people)

fungal infections of the mouth or throat, such as thrush

swelling of lymph glands

sleepiness

ear pain, ear problems

hyperventilating, low oxygen levels in your blood, sinusitis

diarrhoea, pain in and around the stomach

red pustules, papules on the skin

nettle rush, itching

back pain

generally feeling unwell

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed

in this leaflet. You can also report side effects directly via the Yellow Card Scheme at:

www.mhra.gov.uk/yellowcard.

By reporting side affects you can help provide more information on the safety of this medicine.

5.

How to store Vantobra

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the ampoule or the pouch or carton after

EXP. The expiry date refers to the last day of that month.

Store in a refrigerator (2°C - 8°C). If you don’t have a refrigerator available (such as when you are

transporting your medicine) you can store the carton with the medicine (pouches opened or unopened)

below 25°C for up to 4 weeks. If the product has been stored at room temperature for longer than 4

weeks, it has to be disposed according to local requirements.

Do not use this medicine if you notice that it has become cloudy, or if there are particles in the solution.

Never store an opened ampoule. Once opened an ampoule should be used immediately, and any

remaining product should be discarded.

Do not throw away any medicines via household waste. Ask your pharmacist how to throw away

medicines you no longer use. These measures will help to protect the environment.

6.

Contents of the pack and other information

What Vantobra

contains

The active substance is tobramycin. One ampoule contains 170 mg of tobramycin as a single dose.

The other ingredient(s) (excipient(s)) are: sodium chloride, calcium chloride, magnesium sulphate,

water for injections, sulphuric acid and sodium hydroxide for pH adjustment.

What Vantobra

looks like and contents of the pack

Vantobra

nebuliser solution is provided in a ready-to-use ampoule.

Vantobra

is a clear to slightly yellow coloured solution which can vary to a darker yellow. This does not

change how Vantobra

works provided that the storage instructions have been followed.

Ampoules are packed in pouches, one pouch contains 8 ampoules which correspond with 4 days of

treatment.

Vantobra

is available together with a Tolero

nebuliser handset. It is supplied in a carton that contains two

inner cartons, one with the medicine (56 ampoules with nebuliser solution in 7 pouches), and one with the

nebuliser handset. A package is sufficient for one treatment cycle of 28 days.

Marketing Authorisation Holder and Manufacturer

PARI Pharma GmbH

Moosstrasse 3

D-82319 Starnberg

Germany

Tel.:

+49 (0) 89 – 74 28 46 - 10

Fax:

+49 (0) 89 – 74 28 46 30

E-Mail:

info@paripharma.com

For any information about this medicine, please contact the local representative of the Marketing

Authorisation Holder:

United Kingdom

PARI Medical Ltd.

Tel: + 44 (0)1932 3411 22

This leaflet was last revised in: March 2016

Other sources of information

Detailed information on this medicine is available on the European Medicines Agency web site:

http://www.ema.europa.eu. There are also links to other websites about rare diseases and treatments.

Read the complete document

Object 1

Vantobra 170mg nebuliser solution

Summary of Product Characteristics Updated 01-Sep-2016 | PARI Pharma GmbH

1. Name of the medicinal product

Vantobra 170 mg nebuliser solution

2. Qualitative and quantitative composition

Each single-dose ampoule of 1.7 ml contains 170 mg tobramycin.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Nebuliser solution.

A clear to slightly yellow solution.

4. Clinical particulars

4.1 Therapeutic indications

Vantobra is indicated for the management of chronic pulmonary infection due to Pseudomonas

aeruginosa in patients aged 6 years and older with cystic fibrosis (CF).

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

4.2 Posology and method of administration

Posology

The dose of Vantobra is the same for all patients within the approved age range, regardless of age or

weight. The recommended dose is one ampoule (170 mg/1.7 ml) administered twice daily (i.e. total daily

dose is 2 ampoules) for 28 days. The dose interval should be as close as possible to 12 hours and not less

than 6 hours.

Vantobra is taken in alternating cycles of 28 days. A cycle of 28 days of active therapy (on-treatment

period) and 28 days of rest from treatment (off-treatment period) should be maintained.

Missed doses

In case of a missed dose with at least 6 hours remaining until the next dose, the patient should inhale the

dose as soon as possible. If less than 6 hours remain to the next planned dose, the patient should wait for

the next dose and not inhale more to make up for the missed dose.

Duration of treatment

Treatment should be continued on a cyclical basis for as long as the physician considers the patient is

gaining clinical benefit from the treatment taking into account that long-term safety data are not available

for Vantobra. If clinical deterioration of pulmonary status is evident, additional or alternative anti-

pseudomonal therapy should be considered. See also information on clinical benefit and tolerability in

sections 4.4, 4.8 and 5.1.

Special populations

Elderly patients (≥65 years)

There are insufficient data in this population to support a recommendation for or against dose adjustment.

Renal impairment

There are no data in this population to support a recommendation for or against dose adjustment with

Vantobra. Please also refer to nephrotoxicity information in section 4.4 and excretion information in

section 5.2.

Hepatic impairment

No studies have been performed on patients with hepatic impairment. As tobramycin is not metabolised,

an effect of hepatic impairment on the exposure to tobramycin is not expected.

Patients after organ transplantation

Adequate data do not exist for the use of inhaled tobramycin in patients after organ transplantation. No

recommendation for or against dose adjustment can be made for patients after organ transplantation.

Paediatric population

There is no relevant use of Vantobra in children below 6 years of age.

Method of administration

Inhalation use.

Vantobra is administered by inhalation using the Tolero nebuliser handset provided in the pack. For

detailed instructions on use see section 6.6.

Vantobra must not be administered by any other route or using any other device than the one provided in

the pack. The use of an alternative untested nebuliser system may alter the pulmonary deposition of the

active substance. And this in turn may alter efficacy and safety of the product.

Where patients are receiving several inhaled medicinal products and chest physiotherapy, it is

recommended that Vantobra is used last.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

Ototoxicity

Ototoxicity, manifested as both auditory toxicity (hearing loss) and vestibular toxicity, has been reported

with parenteral aminoglycosides. Vestibular toxicity may be manifested by vertigo, ataxia or dizziness.

Tinnitus may be a sentinel symptom of ototoxicity, and therefore the onset of this symptom warrants

caution.

Auditory toxicity, as measured by complaints of hearing loss or by audiometric evaluations, was observed

with parenteral aminoglycosides and may be considered also for the inhalation route of administration. In

open label studies and post-marketing experience, some patients with a history of prolonged previous or

concomitant use of intravenous aminoglycosides have experienced hearing loss. Physicians should

consider the potential for aminoglycosides to cause vestibular and cochlear toxicity and carry out

appropriate assessments of auditory function during Vantobra therapy.

In patients with a predisposing risk due to previous prolonged systemic aminoglycoside therapy it may be

necessary to consider audiological assessment before initiating Vantobra therapy. If a patient reports

tinnitus or hearing loss during aminoglycoside therapy, the physician should consider referring them for

audiological assessment.

Nephrotoxicity

Nephrotoxicity has been associated with parenteral aminoglycoside therapy. There was no evidence of

nephrotoxicity during clinical trials with inhaled tobramycin and Vantobra. Caution should be exercised

when prescribing Vantobra to patients with known or suspected renal dysfunction. According to current

clinical practice baseline renal function should be assessed. Urea and creatinine levels should be

reassessed after every 6 complete cycles of Vantobra therapy (180 days of nebulised aminoglycoside

therapy).

Monitoring of serum tobramycin concentrations

Patients with known or suspected auditory or renal dysfunction should be monitored for serum

tobramycin concentrations. If oto- or nephrotoxicity occurs in a patient receiving Vantobra, tobramycin

therapy should be discontinued until serum concentration falls below 2 µg/ml.

Serum concentrations greater than 12 µg/ml are associated with tobramycin toxicity and treatment should

be discontinued if concentrations exceed this level.

The serum concentration of tobramycin should only be monitored using validated methods. Finger prick

blood sampling is not recommended due to the risk of contamination of the sample.

Bronchospasm

Bronchospasm can occur with inhalation of medicinal products and has been reported with the use of

nebulised tobramycin. Bronchospasm should be treated as medically appropriate.

The first dose of Vantobra should be used under supervision of a physician, after taking a bronchodilator

if this is part of the current regimen for the patient. FEV

should be measured before and after

nebulisation.

If there is evidence of therapy-induced bronchospasm, the physician should carefully evaluate whether

the benefits of continued use of Vantobra outweighs the risks to the patient. If an allergic response is

suspected, Vantobra should be discontinued.

Neuromuscular disorders

Vantobra should be used with great caution in patients with neuromuscular disorders such as

Parkinsonism or other conditions characterized by myasthenia, including myasthenia gravis, as

aminoglycosides may aggravate muscle weakness due to a potential curare-like effect on neuromuscular

function.

Haemoptysis

Inhalation of nebulised tobramycin solutions may induce a cough reflex. The treatment with Vantobra in

patients with active, severe haemoptysis should be initiated only if the benefits of treatment are

considered to outweigh the risks of inducing further haemorrhage.

Development of resistance

The development of antibiotic-resistant P. aeruginosa and superinfection with other pathogens represent

potential risks associated with antibiotic therapy. Development of resistance during inhaled tobramycin

therapy could limit treatment options during acute exacerbations; this should be monitored.

Other precautions

Patients receiving concomitant parenteral aminoglycoside therapy (or any medicine affecting renal

excretion, such as diuretics) should be monitored as clinically appropriate taking into account the risk of

cumulative toxicity. This includes monitoring of serum concentrations of tobramycin.

Safety and efficacy have not been studied in patients colonised with Burkholderia cepacia.

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed. Based on the interaction profile for tobramycin following

intravenous and aerosolised administration, concurrent and/or sequential use of Vantobra is not

recommended with other medicinal products with nephrotoxic or ototoxic potential, such as:

- amphotericin B, cefalotin, ciclosporin, tacrolimus, polymyxins (risk of increased nephrotoxicity);

- platinum compounds (risk of increased nephrotoxicity and ototoxicity);

Concurrent use of Vantobra with diuretic compounds (such as ethacrynic acid, furosemide, urea or

mannitol) is not recommended. Such compounds can enhance aminoglycoside toxicity by altering

antibiotic concentrations in serum and tissue (see section 4.4).

Other medicinal products that have been reported to increase the potential toxicity of parenterally

administered aminoglycosides include:

- anticholinesterases, botulinum toxin (neuromuscular effects).

In clinical studies patients using inhaled tobramycin continued to take dornase alfa, bronchodilators,

inhaled corticosteroids and macrolides. No evidence of drug interactions with these medicines was

identified.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are limited data from the parenteral use of tobramycin in pregnant women. There are no adequate

data from the use of tobramycin administered by inhalation in pregnant women. Animal studies do not

indicate a teratogenic effect of tobramycin (see section 5.3). However, aminoglycosides can cause foetal

harm (e.g., congenital deafness and nephrotoxicity) when high systemic concentrations are achieved in a

pregnant woman. Systemic exposure following inhalation of Vantobra is very low (see section 5.2). If

Vantobra is used during pregnancy, or if the patient becomes pregnant while taking Vantobra, she should

be informed of the potential hazard to the foetus.

Vantobra should not be used during pregnancy unless the benefits to the mother outweigh the risks to the

foetus or baby.

Breast-feeding

Tobramycin is excreted in human breast milk after systemic administration. The amount of tobramycin

excreted in human breast milk after administration by inhalation is not known, though it is estimated to be

very low considering the low systemic exposure. Because of the potential for ototoxicity and

nephrotoxicity in infants, a decision should be made whether to terminate breast-feeding or discontinue

treatment with Vantobra, taking into account the importance of the treatment to the mother.

Fertility

No effect on male or female fertility was observed in animal studies after subcutaneous administration

(see section 5.3).

4.7 Effects on ability to drive and use machines

Vantobra has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

Summary of the safety profile

In controlled clinical trials with Vantobra the most frequent adverse reactions in cystic fibrosis patients

with P. aeruginosa infection were cough and dysphonia.

Clinical experience with tobramycin nebuliser solutions reports dysphonia and tinnitus in patients treated

with tobramycin. The episodes of tinnitus were transient and resolved without discontinuation of

tobramycin therapy.

Occasionally, patients with a history of prolonged previous or concomitant use of intravenous

aminoglycosides may experience hearing loss. Parenteral aminoglycosides have been associated with

hypersensitivity, ototoxicity and nephrotoxicity (see section 4.4).

Long-term safety data are not available for Vantobra (see also section 5.1).

Tabulated list of adverse reactions

Adverse drug reactions reported for tobramycin nebuliser solution are listed in Table 1.

Adverse drug reactions are listed according to system organ classes in MedDRA. Within each system

organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first.

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. In

addition, the corresponding frequency category is provided using the following convention: Very

common (≥ 1/10); Common (≥ 1/100 to < 1/10); Uncommon (≥ 1/1,000 to < 1/100); Rare (≥ 1/10,000 to

< 1/1,000); Very rare (< 1/10,000).

Table 1 Adverse reactions

System Organ Class

Frequency category

Adverse Reactions

Infections and infestations

Rare

Laryngitis

Very rare

Fungal infection

Oral candidiasis

Blood and lymphatic system disorders

Very rare

Lymphadenopathy

Immune system disorders

Very rare

Hypersensitivity

Metabolism and nutrition disorders

Rare

Anorexia

Nervous system disorders

Rare

Dizziness

Aphonia

Headache

Very rare

Somnolence

Ear and labyrinth disorders

Rare

Hearing loss

Tinnitus

Very rare

Ear pain

Ear disorder

Vascular disorders

Rare

Haemoptysis

Epistaxis

Respiratory, thoracic and mediastinal

disorders

Uncommon

Dyspnoea

Dysphonia

Pharyngitis

Cough

Rare

Asthma

Lung disorder

Chest discomfort

Productive cough

Rhinitis

Bronchospasm

Very rare

Hypoxia

Hyperventilation

Sinusitis

Gastrointestinal disorders

Rare

Vomiting

Mouth ulceration

Nausea

Dysgeusia

Very rare

Diarrhoea

Abdominal pain

Skin and subcutaneous tissue disorders

Rare

Rash

Very rare

Urticaria

Pruritus

Musculoskeletal and connective tissue

disorders

Very rare

Back pain

General disorders and administration

site conditions

Rare

Asthenia

Pyrexia

Pain

Chest pain

Very rare

Malaise

Investigations

Rare

Pulmonary function test

decreased

Paediatric population

There was no difference in the safety profile between pediatric and adult patient population treated with

Vantobra.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows

continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are

asked to report any suspected adverse reactions via the the Yellow Card Scheme at:

www.mhra.gov.uk/yellowcard.

4.9 Overdose

Administration by inhalation results in low systemic bioavailability of tobramycin. Symptoms of aerosol

overdose may include severe hoarseness.

In the event of accidental ingestion of Vantobra, toxicity is unlikely as tobramycin is poorly absorbed

from an intact gastrointestinal tract.

In the event of inadvertent administration of Vantobra by the intravenous route, signs and symptoms of

parenteral tobramycin overdose may occur, including dizziness, tinnitus, vertigo, loss of hearing acuity,

respiratory distress and/or neuromuscular blockage and renal impairment.

Acute toxicity should be treated with immediate withdrawal of Vantobra and baseline tests of renal

function should be undertaken. Assessment of tobramycin serum concentrations may be helpful in

monitoring overdose. In the case of any overdose, the possibility of drug interactions with alterations in

the elimination of Vantobra or other medicinal products should be considered.

5. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antibacterials for systemic use, Aminoglycoside antibacterials.

ATC code: J01GB01

Mechanism of action

Tobramycin is an aminoglycoside antibiotic produced by Streptomyces tenebrarius. It acts primarily by

disrupting protein synthesis leading to altered cell membrane permeability, progressive disruption of the

cell envelope and eventual cell death. It is bactericidal at concentrations equal to or slightly greater than

inhibitory concentrations.

Breakpoints

Established susceptibility breakpoints for parenteral administration of tobramycin are inappropriate in the

aerosolised administration of the medicinal product. Sputum of cystic fibrosis patients exhibits an

inhibitory action on the local biological activity of nebulised aminoglycosides. This necessitates sputum

concentrations following treatment with aerosolised tobramycin to be ten to twentyfive-fold above the

Minimum Inhibitory Concentration (MIC) for both P. aeruginosa growth suppression and control of

bactericidal activity. In controlled clinical trials, 97% of patients receiving tobramycin nebuliser solution

achieved sputum concentrations 10-fold of the highest P. aeruginosa MIC cultured from the patient and

95% of patients receiving tobramycin nebuliser solution achieved 25-fold of the highest MIC.

Susceptibility

In the absence of conventional susceptibility breakpoints for the nebulised route of administration,

caution must be exercised in defining organisms as susceptible or insusceptible to nebulised tobramycin.

In clinical studies with TOBI, most patients with P. aeruginosa isolates with tobramycin MICs < 128

µg/ml at baseline showed improved lung function following treatment with TOBI. Patients with a P.

aeruginosa isolate with MIC

128 µg/ml at baseline are less likely to show a clinical response.

However, seven of 13 patients (54%) in the placebo-controlled trials who acquired isolates with MICs of

128 µg/ml while using TOBI had improvement in pulmonary function.

Based upon in-vitro data and/or clinical trial experience, the organisms associated with pulmonary

infections in CF may be expected to respond to Vantobra therapy as follows:

Susceptible

Pseudomonas aeruginosa

Haemophilus influenzae

Staphylococcus aureus

Insusceptible

Burkholderia cepacia

Stenotrophomonas maltophilia

Alcaligenes xylosoxidans

Treatment with the 28-days on and 28-days off dose regimen in clinical studies showed a small but clear

increase in tobramycin, amikacin and gentamicin MICs for P. aeruginosa isolates tested. Each additional

6 months of treatment resulted in incremental increases similar in magnitude to that observed in the 6

months of controlled studies. The most prevalent aminoglycoside resistance mechanism seen in P.

aeruginosa isolated from chronically infected CF patients is impermeability, defined by a general lack of

susceptibility to all aminoglycosides. P. aeruginosa isolated from CF patients has also been shown to

exhibit adaptive aminoglycoside resistance that is characterised by a reversion to susceptibility when the

antibiotic is removed.

Other information

There is no evidence that patients treated with up to 18 months with tobramycin nebuliser solution were at

a greater risk for acquiring B. cepacia, S. maltophilia or A. xylosoxidans, than would be expected in

untreated patients. Aspergillus species were more frequently recovered from the sputum of treated

patients; however, clinical sequelae such as Allergic Bronchopulmonary Aspergillosis (ABPA) were

reported rarely and with similar frequency as in the control group.

Aerosol characteristics

Table 2: Comparative performance data for the clinical test and reference batches:

Vantobra /Tolero nebuliser handset

1

, and TOBI/PARI LC PLUS

2

.

Performance parameter/ Drug/Device combination*

Vantobra/Tolero

TOBI/PARI LC

PLUS

Total Drug Delivered [mg±SD]

96 ± 4.4

101 ± 8.5

Fine Particle Mass < 5 µm [mg±SD]

72 ± 6.5

65 ± 7.1

Drug Delivery Rate [mg/min]

27 ± 5.0

7 ± 0.9

Mass Median Aerodynamic Diameter [µm ± SD]

3.8 ± 0.3

3.6 ± 0.4

Geometric Standard Deviation ±SD

1.5 ± 0.0

2.3 ± 0.2

Nebulisation Time [min]

3.9 ± 0.6

15.3 ± 0.6

*Results from breath simulation and cascade impactor measurements.

connected with an eBase controller or eFlow rapid controller

connected with a PARI Boy SX compressor

The drug delivery rate of Vantobra with the Tolero nebuliser is independent of the breathing pattern

applied i.e. adult or child in contrast to the PARI LC PLUS nebuliser.

Clinical efficacy and safety

Limited data from one controlled clinical study over one treatment cycle indicate that the improvement in

lung function was maintained above baseline during the 28-day off-treatment period.

As a result of study 12012.101, lung function improvement FEV

% predicted relative to baseline

increased by 8.2 ± 9.4% under Vantobra and by 4.8 ± 9.6% under the reference therapy in the first

treatment cycle showing non-inferior (p=0.0005) efficacy. CFU reduction as an indicator for suppression

of P. aeruginosa was comparable for Vantobra and the reference product.

5.2 Pharmacokinetic properties

Absorption and distribution

The systemic exposure to tobramycin after inhalation of Vantobra is expected to emerge primarily from

the inhaled portion of the medicinal product as tobramycin is not absorbed to any appreciable extent when

administered via the oral route.Inhalation of nebulised tobramycin produces high sputum concentrations

and low plasma levels.

For comparative aerosol data please refer to Table 2 in section 5.1

At the end of a 4-weeks dosing cycle of Vantobra (170 mg/1.7 ml twice daily) in cystic fibrosis patients,

maximum tobramycin plasma concentrations (Cmax) of 1.27 ± 0.81 µg/ml were reached at approximately

one hour after inhalation. Sputum concentrations were higher and more variable with Cmax of 1,951 +

2,187 µg/g. After administering a single dose of Vantobra 170 mg to healthy volunteers Cmax of 1.1 +

0.4 µg/ml were reached after a tmax of approximately 4 hours.

Distribution

Less than 10% of tobramycin is bound to plasma proteins.

Biotransformation

Tobramycin is not metabolised and is primarily excreted unchanged in the urine.

Elimination

The elimination of tobramycin administered by the inhalation route has not been studied.

Following intravenous administration, systemically absorbed tobramycin is eliminated by glomerular

filtration. The elimination half-life of tobramycin from serum is approximately 2 hours.

Unabsorbed tobramycin following administration by inhalation is probably eliminated primarily in

expectorated sputum.

5.3 Preclinical safety data

Non-clinical data reveal that the main hazard for humans, based on conventional studies of safety

pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction

and development, consists of renal toxicity and ototoxicity. In repeated dose toxicity studies it has been

shown that target organs of toxicity are the kidneys and vestibular/cochlear functions. In general, toxicity

is seen at higher systemic tobramycin levels than are achievable by inhalation of the recommended

clinical dose.

No reproduction toxicology studies have been conducted with tobramycin administered by inhalation.

Subcutaneous administration at doses of 100 mg/kg/day in rats and the maximum tolerated dose of 20

mg/kg/day in rabbits during organogenesis was not teratogenic. Teratogenicity could not be assessed at

higher parenteral doses in rabbits as they induced maternal toxicity and abortion. Based on available data

from animals a risk of toxicity (e.g. ototoxicity) at prenatal exposure levels cannot be excluded.

Tobramycin did not impair fertility in male or female rats at subcutaneous doses up to 100 mg/kg/day.

6. Pharmaceutical particulars

6.1 List of excipients

Sodium chloride

Calcium chloride

Magnesium sulphate

Sulphuric acid (for pH adjustment)

Sodium hydroxide (for pH adjustment)

Water for injections

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal

products in the nebuliser.

6.3 Shelf life

3 years

The contents of a single-dose ampoule should be used immediately after opening (see section 6.6).

Stability after opening of the pouch: 4 weeks when stored below 25 °C

6.4 Special precautions for storage

Store in a refrigerator (2 °C – 8 °C).

For storage conditions after first opening of the medicinal product, see section 6.3.

6.5 Nature and contents of container

Vantobra is supplied in polyethylene (PE) ampoules that are packed in sealed aluminium foil pouches (8

ampoules per pouch).

Outer carton contains:

One carton with the medicinal product: 56 ampoules with nebuliser solutionin 7 pouches.

One carton with the Tolero nebuliser handset.

6.6 Special precautions for disposal and other handling

The contents of one ampoule should be emptied into the medication reservoir of the Tolero nebuliser

handset and administered by inhalation until no medicine is left in the reservoir. The Tolero nebuliser

handset can be operated either with an eBase controller or with the eFlow rapid control unit. The

performance parameters from in vitro aerosol characterisation studies are identical for the two controllers

and are shown in section 5.1, Table 2.

Nebulisation should take place in a well ventilated room.

The nebuliser handset must be kept horizontally during operation.

The patient should sit in an upright position during inhalation. Inhalation should be performed by

applying a normal breathing pattern without interruption.

The Tolero nebuliser handset must be cleaned and disinfected as described in the instructions for use of

the device.

Vantobra is a clear to slightly yellow solution, but some variability in colour may be observed, which

does not indicate loss of activity if the product is stored as recommended.

Vantobra solution is a sterile, aqueous preparation for single use only. As it is preservative-free, the

contents of the whole ampoule should be used immediately after opening and any unused solution should

be discarded. Opened ampoule should never be stored for re-use.

Use a new Tolero nebuliser handset for each treatment cycle (28 days on-treatment) as provided with the

medicine.

Any unused medicinal product or waste material should be disposed off in accordance with local

requirements.

7. Marketing authorisation holder

PARI Pharma GmbH

Moosstrasse 3

D-82319 Starnberg

Germany

Tel.:

+49 (0) 89 - 74 28 46 - 10

Fax:

+49 (0) 89 - 74 28 46 - 30

E-Mail:

[email

protected]

8. Marketing authorisation number(s)

EU/1/14/932/001

9. Date of first authorisation/renewal of the authorisation

18 March 2015

10. Date of revision of the text

March 2016

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.

Legal category

Company Contact Details

PARI Pharma GmbH

Address

Moosstraße 3,, Starnberg, Germany

Telephone

+49 8151 279-0

Medical Information Direct Line

+49 (0) 89-742 846-51 or +49 (0) 89 742 846-832

Medical Information Fax

+49 (0) 89-742 846-30

http://www.paripharm.com

+49 8151 279-101

Medical Information e-mail

[email

protected]

Medical Information Fax

[email

protected]

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